3-Amino-4-hydroxy(or alkoxy)phenethanolamine derivatives and _pharmacologically acceptable acid addition salts thereof for _increasing the growth rate and/or improving the lean meat to fat _ratio of warm-blooded animals

ABSTRACT

A method for increasing the growth rate and/or improving the lean meat to fat ratio in farm and domestic animals. An effective amount of a 3-amino-4-hydroxy(or alkoxy)phenethanolamine derivative, pharmacologically-acceptable acid addition or metal salt thereof is administered either orally or parenterally to animals. Novel 3-amino-4-hydroxy(or alkoxy)phenethanolamine derivatives are also described.

This is a continuation-in-part of co-pending application Ser. No.326,878, filed Dec. 2, 1981, now U.S. Pat. No. 4,404,224.

The invention herein described relates to a method for increasing thegrowth rate, enhancing the lean meat deposition and/or improving thelean meat to fat ratio in warm-blooded animals, particularly farm anddomestic animals (i.e., swine, poultry, cattle, sheep, goats, rabbits,cats, dogs, etc.). The method involves either oral or parenteraladministration of various 3-amino-4-hydroxy(or alkoxy)phenethanolaminederivatives, including novel derivatives presently revealed.

By way of background, sulfonanilide derivatives, their acid addition andmetal salts are disclosed in U.S. Pat. Nos. 3,341,581 and 3,801,631.These patents reveal that the above-mentioned compounds are useful asadrenergic neurotransmitters, vasopressors, vasodepressors, analgesics,bronchodilators, α-receptor stimulants, β-receptor stimulants,α-receptor blocking agents, β-receptor blocking agents, papaverine-likesmooth muscle depressants and anti-inflammatory agents.

In addition to the above-said sulfonanilide derivatives, related3-amino-4-hydroxyphenethanolamine derivatives are described with similarpharmacological activities in the following publications: Belgium Pat.Nos. 784,105; 762,504 and 765,988; U.S. Pat. Nos. 3,763,232; 3,917,847and 3,711,545; Journal of Medicinal Chemistry, 10, 762-472 (1967),ibid., 17, 49-57 (1974) and ibid., 19, 626-633 (1976).

In recent years, the cost of raising meat animals has increased markedlyin response to economic fluctuations in the areas of energy resources,ancillary products, and consumer markets. The necessity of providingadequate meat protein supplies to an expanding population isself-evident. A method for increasing the quantity and/or quality ofanimal protein supplies while maintaining ordinary feed requirementswould facilitate delivery of required food supplies.

In light of the foregoing summary of some demands and limitations ofconventional methods for the production of meat products, an improvedmethod for quantative and/or qualitative improvement in animal yields ishighly desirable. An object of this invention is to provide new anduseful compounds and methods of use for increasing the growth rate,enhancing the lean meat deposition, and/or improving the lean meat tofat ratio in farm and domestic animals. This object is manifest in thefollowing description and particularly delineated in the appendedclaims.

It has been unexpectedly discovered that oral or parenteraladministration of selected 3-amino-4-hydroxy(or alkoxy)phenethanolaminederivatives not only will increase the growth rates of certainwarm-blooded animals but also will increase lean meat deposition andimprove the lean meat to fat ratio in the bodies of these animals. Inthis disclosure, the term "lean meat" is used interchangeably with theamount of muscle or protein present in referenced animals. Theabove-mentioned effects are achieved by oral or parenteraladministration to appropriate animals of an effective amount of acompound represented by the following structural formula: ##STR1##wherein, R₁ is hydrogen or C₁ -C₄ alkyl; R₂ is hydrogen, C₁ -C₄ alkyl,cycloalkyl C₃ -C₅, benzyl, phenethyl, α-methylphenethyl orα,α-dimethylphenethyl; R₃ is OH, OR₆ or SR₇ ; R₄ is hydrogen, C₁ -C₄alkyl, benzyl or C₂ -C₅ alkanoyl; R₅ is hydrogen, methyl or ethyl; R₆ isC₁ -C₆ alkyl, benzyl, phenyl or allyl; R₇ is hydrogen, C₁ -C₆ alkyl,benzyl, phenyl or allyl; X is NHSO₂ R₈, N(SO₂ R₈)₂, N(R₁)₂, NHCOR₁,NH--CO--N(R₁)₂, NSO₂ N(R₁)₂, NHCOOR₉, or NHCOO-benzyl; R₈ is C₁ -C₄alkyl; R₉ is C₁ -C₅ alkyl; with the provisos that when R₂ is cycloalkylC₃ -C₅, benzyl, phenethyl, α-methylphenethyl or α,α-dimethylphenethyl,R₁ of NR₁ R₂ is hydrogen; and when R₃ is OR₆ or SR₇, X is only NHSO₂ R₇; and further that the R₁ group in (R₁)₂ may or may not be identicalsubstituents; and the optically active isomers and pharmacologicallyacceptable acid addition and metal salts thereof.

A preferred group of compounds of this invention, as depicted by formulaI above, are those wherein R₄ is hydrogen; R₃ is OH; R₅ is hydrogen; R₁is hydrogen or C₁ -C₄ alkyl; R₂ is hydrogen, C₁ -C₄ alkyl,α,α-dimethylphenethyl or α-methylphenethyl; X is NHSO₂ CH₃, N(R₁)₂,NHCOR₁, NH--CO--N(R₁)₂, NSO₂ N(R₁)₂ or NHCOOR₉, where R₉ is C₁ -C₅alkyl; with the provisos that when R₂ is α-methylphenethyl orα,α-dimethylphenethyl, R₁ in NR₁ R₂ is hydrogen; and further that bothR₁ 's in (R₁)₂ may be the same or different substituents; and theoptically active isomers and pharmacologically acceptable acid additionand metal salts thereof.

A still more preferred group of compounds of the present invention havethe structure depicted by Formula II: ##STR2## wherein R₁ is hydrogen orC₁ -C₄ alkyl; R₂ is C₁ -C₄ alkyl or α,α-dimethylphenethyl; with theproviso that when R₂ is α,α-dimethylphenethyl, R₁ of NR₁ R₂ is hydrogen;and the optically active isomers and pharmacologically acceptable acidaddition and metal salts thereof.

Among the pharmacologically acceptable acid addition salts useful in thepresent invention are the hydrochloride, sulfate, phosphate, gluconate,succinate, propionate, oleate, linoleate, linolenate, fumarate andabiate salts.

Novel compounds of the present invention are depicted by the structureshown as Formula III below: ##STR3## wherein X is NHSO₂ R₈ or N(SO₂ R₈)₂; R₁ is hydrogen or C₁ -C₄ alkyl; R₂ is hydrogen, C₁ -C₄ alkyl, benzyl,phenethyl, α-methylphenethyl or α,α-dimethylphenethyl; R₃ is OR₆ or SR₇; R₆ is C₁ -C₄ alkyl, benzyl, phenyl or allyl; R₇ is hydrogen, C₁ -C₆alkyl, benzyl, phenyl or allyl; R₈ is C₁ -C₄ alkyl; with the provisosthat when R₂ is benzyl, phenethyl, α-methylphenethyl orα,α-dimethylphenethyl, R₁ of NR₁ R₂ is hydrogen; and when X is N(SO₂R₈)₂, R₃ is OH; and the optionally active isomers and pharmacologicallyacceptable acid addition and metal salts thereof.

A preferred group of these novel formula III compounds are those whereinR₃ is OR₆ and R₁, R₂, R₆, R₈, and X are as described above for formulaIII compounds.

Another preferred group of these novel formula III compounds are thosewherein R₃ is SR₇ and R₁, R₂, R₇, R₈, and X are as described above forformula III compounds.

Advantageously, the compounds of this invention as delineated byformulas I, II, and III above, generally can be prepared by one or moreof the synthetic routes described in the above-identified publicationand graphically illustrated below. ##STR4##

In the above reactions, R₁ in the function (R₁)₂ may represent the sameor different substitutents selected from hydrogen and C₁ -C₄ alkyl andR₄ is C₂ -C₅ acyl.

The above-illustrated acetophenone compounds may be converted by thereactions, graphically illustrated below, to compounds of the inventionhaving the formula I structure in which R₃ is OH, R₁ is hydrogen and X,R₂, R₄, and R₅ are as described for formula I compounds depicted above.##STR5##

In the above reaction, X, R₁, R₂, R₄, and R₅ are as defined with respectto formula I

Additionally, the novel 2'hydroxy-5'-[1-alkoxy-2-(alkyl-, dialkyl- oraralkylamino)ethyl]alkanesulfonanilides of this invention can beprepared by the following steps:

(1) reacting a2'-hydroxy-5'-[1-hydroxy-2-(alkylamino)ethyl]alkanesulfonanilide or thedialkylamino or aralkylamino derivative thereof, with an equivalentamount or slight excess of thionyl chloride to obtain the2'-hydroxy-5'-[1-chloro-2-(alkyl-, dialkyl- oraralkylamino)ethyl]alkanesulfonanilide hydrochloride;

(2) converting the above-formed alkanesulfonanilide hydrochloride saltto the 2'-hydroxy-5'-[1alkoxy-2-(alkyl-, dialkyl- oraralkylamino)ethyl]alkanesulfonanilide hydrochloride by reacting thehydrochloride salt with the appropriate C₁ -C₆ alcohol at temperaturebetween about 0° to 150° C.; and

(3) when a free base of an above-named hydrochloride-salt compound isdesired, it is obtained by neutralization of the hydrochloride salt witha suitable aqueous base (i.e., sodium hydroxide, potassium hydroxideetc.).

The 2'-hydroxy-5'-[1-alkoxy-2-(alkyl-, dialkyl- oraralkylamino)ethyl]alkanesulfonanilide derivatives and salts as well as2'-hydroxy-5'-[1-benzyloxy-2-(alkyl-, dialkyl- oraralkylamino)ethyl]alkanesulfonanilide derivatives and salts are readilyprepared by the above-described procedures and further illustrated inthe following equations: ##STR6## wherein R₁ is hydrogen or C₁ -C₄alkyl; R₂ is hydrogen, C₁ -C₄ alkyl, benzyl, phenethyl,α-methylphenethyl or α,α-dimethylphenethyl; R₈ is C₁ -C₄ alkyl and R₆ isC₁ -C₆ alkyl, benzyl, phenyl or allyl; with the condition that when R₂is benzyl, phenethyl, α-methylphenethyl or α,α-dimethylphenethyl, R₁ ofNR₁ R₂ is hydrogen.

The 2'-hydroxy-5'-[1-phenoxy-2-(alkyl-, dialkyl- oraralkylamino)ethyl]alkanesulfonanilide compounds can be prepared byreacting an appropriate 2'-hydroxy-5'-[1-chloro-2-(alkyl-, dialkyl- oraralkylamino)ethyl]alkanesulfonanilide compounds with an excess amount(i.e., preferably 10 to 15 equivalents) of an alkali metal phenoxide inthe presence of an aprotic solvent (i.e., tetrahydrofuran, ether,toluene, benzene, etc.). This reaction is carried out at a temperaturebetween about -5° and +10° C. under a blanket of an inert gas.

The 2'-hydroxy-5'-[1-alkyl, benzyl-, or allylthio)-2-(alkyl-, dialkyl-,or aralkylamino)ethyl]alkanesulfonanilide compounds of the invention canbe prepared by reacting an appropriate2'-hydroxy-5'-[1-chloro-2-(alkyl-, dialkyl-, oraralkylamino)ethyl]alkanesulfonanilide hydrochloride with an equimolaror excess amount of an alkyl, benzyl or allylmercaptan (i.e., R₆ SH).

This reaction is illustrated by the following equation: ##STR7## whereinR₁ is hydrogen or C₁ -C₄ alkyl, R₂ is hydrogen, C₁ -C₄ alkyl, benzyl,phenethyl, α-methylphenethyl or α,α-dimethylphenethyl; R₈ is C₁ -C₄alkyl; R₇ is hydrogen, C₁ -C₆ alkyl, benzyl, or allyl. This reaction isgenerally conducted in the presence of an aprotic solvent (i.e., achlorinated hydrocarbon such as ether or other similar material) at atemperature ranging from -5° to +50° C. under a blanket of an inert gas.

The 2'-hydroxy-5'-[1-phenylthio-2-(alkyl-, dialkyl-, oraralkylamino)ethyl]alkanesulfonanilides can be prepared by reacting anappropriate 2'-hydroxy-5'-[1-chloro-2-(alkyl-, dialkyl-, oraralkylamino)ethyl]alkanesulfonanilide compound with an excess amount ofan alkali metal thiophenoxide (i.e., sodium or potassium thiophenoxide)in an aprotic solvent (i.e., tetrahydrofuran, benzene, toluene or ether)at a temperature ranging from about -5° to +10° C. under a blanket of aninert gas.

The formula I compounds of this invention can generally be administeredeither orally or parenterally to domestic or farm animals with resultantincreases in growth rates and enhancement of the lean meat to fat ratioin these animals. In actual practice, the formula I compounds may bedirectly mixed with animal feeds or prepared in the form of ananimal-feed premix, concentrate, or supplement which can be blended withor applied as a top dressing to animal feeds. Regardless of theprocedure selected, the active compound should be present at levels fromabout 0.05 to 500 ppm and preferably 0.1 to 100 ppm in the feed.

Animal-feed premixes, supplements or concentrates can be prepared bymixing on a weight basis about 0.5 to 50% of a suitable formula Icompound with about 50 to 99.5% of an edible diluent. Diluents suitablefor use in the manufacture of animal-feed supplements, concentrates, andpremixes include the following: corn meal, soybean meal, bone meal,alfalfa meal, cottonseed oil meal, urea, molasses, and other similarmaterials. Use of the diluents in feed supplements, concentrates, andpremixes improves uniformity of distribution of the active ingredient inthe finished feed.

Feeds for swine, cattle, sheep, and goats preferably contain about 0.05to 400 grams of active ingredient per ton of feed with an optimum levelof about 0.25 to 100 grams per ton. Preferred poultry and domestic-petfeeds range from about 0.05 to 400 grams and most preferably 0.2 to 100grams of active ingredient per ton of feed.

When parenteral administration is desired, formula I compounds may beformulated as pastes or pellets and adminstered to the animals bysubcutaneous injection. This procedure involves injection of a formula Icompound in an amount sufficient to provide the animal with 0.001 to 100mg/kg of body weight/day of the active compound. The preferred dosagefor swine, cattle, sheep, and goats ranges from about 0.0001 to 50mg/day/kg of body weight of the active formula I compound. The preferreddosage for poultry and domestic pets ranges from about 0.001 to 10mg/day/kg of body weight.

Paste formulations suitable for subcutaneous injection can be preparedby dispersing formula I compound in a pharmacologically acceptable oil(i.e., peanut oil, corn oil, seasame oil, etc.). Pellets forsubcutaneous injection can be prepared by mixing a formula I compoundwith a suitable diluent (i.e., carbowax, carnauba wax, etc.). Alubricant (i.e., magnesium or calcium stearate) can be added to improvethe pelleting process.

In order to obtain the drug dosage levels necessary to achieve desiredresults (i.e., increase in growth rates and improvement in lean meat tofat rates), it may be necessary to administer multiple pellets. Also,implants may be made periodically during treatment periods in order tomaintain proper animal drug levels.

In addition to improved growth rates and enhanced lean meat to fatratios, administration of formula I compounds to meat-producing animalsfrequently results in enhanced efficiency of feed utilization thereby.With the use of materials and methods revealed in the present invention,producers can market superior quality meat animals in a short period oftime while incurring minimum feed costs.

The following non-limiting examples further serve to illustrate theinvention.

EXAMPLE 1 Preparation of2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilidehydrochloride

A 1-g sample of2'-hydroxy-5'-[1-hydroxy-2-(isopropylamino)ethyl]methanesulfonanilide isadded to 2 mL of ice-cold thionyl chloride. The mixture is then stirredat ambient temperature until the reaction is completed. Excess thionylchloride is removed in vacuo, and the residue is washed with ethyl etherthus yielding the product compound.

The compound2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilidehydrochloride can also be prepared by heating 1 g of2'-hydroxy-5'-[1-hydroxy-2-(isopropylamino)ethyl]methanesulfonanilide in10 mL of dry acetonitrile or dry dimethoxyethane containing 2 mL ofthionyl chloride at reflux temperature for 10 minutes following theprocedure described in the Journal of Medicinal Chemistry, 19, 632(1976).

EXAMPLE 2 Preparation of2'-hydroxy-5'-[1-ethoxy-2-(isopropylamino)ethyl]methanesulfonanilidehydrochloride

A 1-g sample of2'-hydroxy-5'-[1-chloro-2-isopropylamino)ethyl]methanesulfonanilidehydrochloride is added to 10 mL of absolute ethanol and heated at refluxfor 30 minutes. The mixture is evaporated to dryness, and the residue iswashed with ethyl ether thus yielding the product compound. The sameprocedure is used to prepare2'-hydroxy-5'-[1-isopropoxy-2-(isopropylamino)ethyl]methanesulfonanilidehydrochloride, m.p. 121-123, by substituting isopropanol for ethanol inthe above reaction.

Neutralization of the2'-hydroxy'5'-[1-ethoxy-2-(isopropylamino)ethyl]methanesulfonanilidehydrochloride salt with aqueous sodium hydroxide yields the free base ofthis compound which can be separated from the aqueous solution andreadily converted to other acid salts by tritration.

EXAMPLE 3 Preparation of chloro intermediates

Several chloro intermediates can be prepared by the method of Example 1as illustrated in the following equation: ##STR8## wherein substituentsare:

    ______________________________________                                        R.sub.1    R.sub.2           R.sub.8                                          ______________________________________                                        H          t-butyl           methyl                                           H          n-propyl          methyl                                           H          i-propyl          n-butyl                                          methyl     methyl            methyl                                           H          benzyl            methyl                                           H          t-butyl           n-propyl                                         ethyl      ethyl             methyl                                           H          phenethyl         methyl                                           H          α, α-dimethylphenethyl                                                              methyl                                           ______________________________________                                    

EXAMPLE 4 Preparation of ethers

Several ethers can be prepared according to the method of Example 2 asillustrated in the following equation: ##STR9## wherein substituentsare:

    ______________________________________                                        R.sub.2           R.sub.6    M.P.°C.                                   ______________________________________                                        isopropyl         methyl                                                      isopropyl         benzyl                                                      isopropyl         allyl                                                       t-butyl           ethyl                                                       isopropyl         isopropyl  121-123                                          phenethyl         ethyl                                                       α, α-dimethylphenethyl                                                              methyl                                                      α, α-dimethylphenethyl                                                              ethyl                                                       isopropyl         n-butyl                                                     isopropyl         n-hexyl                                                     α, α-dimethylphenethyl                                                              isopropyl  210-212                                          ______________________________________                                    

EXAMPLE 5 Preparation of2'-hydroxy-5'-[phenoxy-2-(isopropylamino)ethyl]methanesulfonanilide

A 3.25 g sample of2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilidehydrochloride is slowly added to 45 g of sodium phenoxide in 150 mL ofdry tetrahydrofuran at 0° to 5° C. under N₂ atmosphere. The mixture isstirred for 24 hours at ambient temperature and then poured on icewhereafter the crude product compound is separated.

EXAMPLE 6 Preparation of2'-hydroxy-5'-[1-phenylthio-2-(isopropylamino)ethyl]methanesulfonanilide

The compound2'-hydroxy-5'-[1-phenylthio-2-(isopropylamino)ethyl]methanesulfonanilidecan be prepared following the method described in Example 5 with thesubstitution of sodium thiophenoxide for sodium phenoxide.

EXAMPLE 7 Preparation of2'-hydroxy-5'-[1-methylthio-2-(isopropylamino)ethyl]methanesulfonanilide

A 1-g sample of2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilidehydrochloride is slowly added to 5 mL of methylmercaptan in 25 mL ofethylene dichloride at 0° to -10° C. under N₂ atmosphere. This mixtureis first stirred several hours at ice-bath temperature and then stirredat ambient temperature for 24 hours. The mixture is filtered. The filtercake is washed with ethylene dichloride, added to water, and basifiedwith 10% NaOH solution to pH 10 in an ice bath. The aqueous mixture isextracted several times with methylene chloride. The combined extractsare dried over MgSO₄ and evaporated to dryness thus yielding the crudeproduct compound.

EXAMPLE 8

Several thioethers can be prepared using the method of Example 7 asillustrated in the following equation: ##STR10## wherein substituentsare:

    ______________________________________                                        R.sub.2                R.sub.7                                                ______________________________________                                        isopropyl              isopropyl                                              isopropyl              benzyl                                                 t-butyl                methyl                                                 phenethyl              methyl                                                 α, α-dimethylphenyl                                                                      methyl                                                 isopropyl              ethyl                                                  isopropyl              allyl                                                  ______________________________________                                    

Use of NaSH in place of R₇ SH without further basification yields:##STR11##

EXAMPLE 9 2'-Acetoxy-5'-[2-(isopropylamino)-1-hydroxyethyl]anilinehydrochloride

A mixture containing 36.2 g (0.2 mole) of4'-hydroxy-3'-nitroacetophenone, 15.7 g of acetyl chloride, 22 mL of 50%KOH solution, 200 mL of H₂ O and 300 mL of 95% ethanol is stirred andheated to reflux for 18 hours. The mixture is evaporated to removeethanol, and the aqueous mixture is extracted with CHCl₃ to solubilizethe product. The CHCl₃ extract is evaporated to dryness to afford4'-acetoxy-3'-nitroacetophenone, which is brominated with an equimolarquantity of Br₂ in CHCl₃ (100 mL) to afford2-bromo-4'-acetoxy-3-nitroacetophenone. This phenacyl bromide is thenreacted in 100 mL of ethanol with 2 equivalents of isopropylamine toafford 4'-acetoxy-3'-nitro-2-isopropylaminoacetophenone, which isolatedas the hydrochloride by the procedure reported by Larson et al. inJournal of Medicinal Chemistry, 10, 467 (1967) for a related compound.This ketoamine is then hydrogenated in 90% aqueous ethanol with 0.5 g of10% Pd-C/3.5 kg/cm² H₂ pressure in a Parr hydrogenator until the uptakeof H₂ is completed. The mixture is filtered, and the filtrate isevaporated to dryness to afford the crude title compound.

Similarly, substitution of pivaloyl chloride, butyryl chloride,propionyl chloride, isobutyryl chloride, and valeryl chloride in placeof acetyl chloride in the above sequence affords the corresponding2'-pivaloyoxy-, 2'-butyryloxy-2'-propionyloxy-, 2'-isobutyryloxy-, and2'-valeryloxy-5'-[2-(isopropylamino)-1-hydroxyethyl]anilinehydrochlorides. Similarly, substitution of the isopropylamine byt-butylamine, 2-butylamine, ethylamine, n-propylamine, cyclopentylamineand α,α-dimethylphenethylamine affords the following compounds:##STR12##

EXAMPLE 102'-Pivaloyloxy-5-[1-hydroxy-2-(α,α-dimethylphenethylamino)ethyl]methanesulfonanilide

2'-Pivaloyloxy-3'-nitroacetophenone (10 g), which is prepared by themethod described in Example 9, in 200 mL of MeOH is reduced in a Parrhydrogenator with 0.2 g of PtO₂. The mixture is filtered, and thesolvent is removed to afford crude 2'-pivaloyoxy-3'-aminoacetophenone.This material is stirred in 75 mL of pyridine and 4.32 g ofmethanesulfonyl chloride is added dropwise at 25° C. After three hours,the mixture is poured into an ice water mixture, and the precipitate iscollected and washed with H₂ O, dilute HCl and H₂ O successively toafford 2'-pivaloyloxy-5'-acetylmethanesulfonanilide. This material isthen brominated by the procedure of Example 9 to afford2'-pivaloyloxy-5'-(2-bromoacetyl)methanesulfonanilide, which is thenreacted with isopropylamine according to the procedure of Example 9 toafford 2'-pivaloyloxy-5'-(2-isopropylaminoacetyl)methanesulfonanilidehydrochloride. This intermediate is then reduced by the procedure ofExample 9 to yield 2'-pivaloyloxy-5'-[(2-isopropylamino)-1-hydroxyethyl]methanesulfonanilidehydrochloride.

Similarly, the following compounds are prepared by the above sequencewith or without different acyl chlorides (R₄ Cl) for pivaloyl chlorideand with or without substitution of R₁ R₂ NH for isopropylamine.

    ______________________________________                                         ##STR13##                                                                        R.sub.4   R.sub.1       R.sub.2                                           ______________________________________                                        CH.sub.3 CO                                                                             H             isopropyl                                             CH.sub.3 CO                                                                             H             α,α-dimethylphenethyl                     CH.sub.3 CO                                                                             H             t-butyl                                               C.sub.2 H.sub.5 CO                                                                      H             isopropyl                                             C.sub.2 H.sub.5 CO                                                                      H             α,α-dimethylphenethyl                     C.sub.2 H.sub.5 CO                                                                      H             t-butyl                                               n-C.sub.3 H.sub.7 CO                                                                    H             isopropyl                                             n-C.sub.3 H.sub.7 CO                                                                    H             t-butyl                                               n-C.sub.3 H.sub.7 CO                                                                    H             α,α-dimethylphenethyl                     i-C.sub.3 H.sub.7 CO                                                                    H             isopropyl                                             i-C.sub.3 H.sub.7 CO                                                                    H             α,α-dimethylphenethyl                     i-C.sub.3 H.sub.7 CO                                                                    H             t-butyl                                               pivaloyl  H             t-butyl                                               pivaloyl  H             α,α-dimethylphenethyl                     pivaloyl  H             cyclopentyl                                           pivaloyl  methyl        methyl                                                ______________________________________                                    

EXAMPLE 11N-{2-Hydroxy-5-[1-hydroxy-2-(isopropylamino)ethyl]phenyl}dimethanesulfonamide

In 250 mL of CH₂ Cl₂ containing 26 mL of triethylamine, 20 g of3'-amino-4'-benzyloxyacetophenone is stirred at 10° C. and 19 g ofmethanesulfonyl chloride is added gradually. The mixture is then stirredat room temperature for 24 hours and extracted with 10% aqueous NaOHsolution. The CH₂ Cl₂ solution is further washed with H₂ O, dried overMgSO₄, and evaporated in vacuo until crystallization begins to occur.The dimethanesulfonamide derivative (A) is then collected. In 100 mL ofdioxane containing 7 mL of H₂ O, and 7 mL of H₂ O, and 8.2 g of seleniumdioxide, compound A is added gradually at 70° C. Heating is continuedfor an overnight period, and the mixture is heated at reflux for anhour. The mixture is decolorized with activated carbon, filtered, andevaporated to dryness in vacuo. The residual oil is mixed with 500 mL ofCH₂ Cl₂ and washed twice with 100 mL of H₂ O. The CH₂ Cl₂ solution isdried over MgSO₄ and evaporated to dryness to afford the crude glyoxal,which is further dissolved in 100 mL of CH₂ Cl₂. A half of this solutionis stirred, and 3.2 mL of isopropyl amine is gradually added. After onehour, the mixture is evaporated to dryness; the residue is trituratedwith ether and filtered. This solid is stirred in 250 mL of ethanol at15° C. and 2.4 g of NaBH₄ is added in one portion. The mixture isstirred at room temperature overnight and evaporated to dryness. Theresidual solid is heated in 200 mL of boiling CH₂ Cl₂ and filtered. Thiswashing procedure is repeated twice. The remaining residue is partiallydissolved in 30 mL of CH₂ Cl₂, and the mixture is washed with H₂ O(3×200 mL). The CH₂ Cl₂ solutions are combined, washed with H₂ O (3×300mL), dried over MgSO₄, and evaporated to dryness to afford a yellow oil.This oil is triturated with Et₂ O to afford 5.5 g of pale-yellow solid(B) after filtration. A 5-gram sample of B is added to 200 mL of MeOHcontaining 1 g of 5% Pd-C and hydrogenated at 50-45 p.s.i.g. untiluptake of H₂ is completed. The mixture is filtered; the catalyst iswashed with 50 mL of MeOH, and the methanol solutions are evaporated todryness to afford the crude title compound, which is washed with ether;m.p. 174° C.

The following compounds are prepared in the above manner with or withoutsubstitution of methanesulfonyl chloride with the appropriate R₈ SO₂ Cland with or without substitution of isopropylamine with R₂ NH₂.

    ______________________________________                                         ##STR14##                                                                           R.sub.8       R.sub.2                                                  ______________________________________                                        C.sub.2 H.sub.5  isopropyl                                                    methyl           t-butyl                                                      methyl           α,α-dimethylphenethyl                            isopropyl        isopropyl                                                    n-butyl          isopropyl                                                    n-butyl          t-butyl                                                      n-butyl          α,α-dimethylphenethyl                            isopropyl        t-butyl                                                      isopropyl        α,α-dimethylphenethyl                            methyl           cyclopentyl                                                  methyl           α-methylphenethyl                                      methyl           ethyl                                                        ______________________________________                                    

EXAMPLE 12 Evaluation of test compounds for increasing the growth rateof animals and enhancing the lean meat to fat ratio thereof by reducingfat deposition in said animals and increasing the lean meat thereof

CIF female mice from Carworth Farms are received when they are six weeksold. They are housed ten to a cage in air-conditioned rooms (22° C. to25° C.) with automatic diurnal illumination (14 hours light and 10 hoursdark). Compounds of the invention are added to a basic diet of PurinaLaboratory Chow which is supplied ad libitum and contains the followingingredients:

                  TABLE I                                                         ______________________________________                                        Description of Diet                                                           Guaranteed Analysis %                                                         ______________________________________                                        Crude protein not less than                                                                       23.0                                                      Crude fat not less than                                                                           4.5                                                       Crude Fiber not more than                                                                         6.0                                                       Ash not more than   9.0                                                       ______________________________________                                    

INGREDIENTS

Meat and bone meal, dried skimmed milk, wheat germ meal, fish meal,animal liver meal, dried beet pulp, ground extruded corn, ground oatgroats, soybean meal, dehydrated alfalfa meal, cane molasses, animal fatpreserved with BHA, vitamin B₁₂ supplement, calcium pantothenate,choline chloride, folic acid, riboflavin supplement, brewer's driedyeast, thiamin, niacin, vitamin A supplement, D-activated plant sterol,vitamin E supplement, calcium carbonate, dicalcium phosphate, iodizedsalt, ferric ammonium citrate, iron oxide, manganous oxide, cobaltcarbonate, copper oxide, zinc oxide. Water is also allowed ad libitum.

Various experimental treatments are randomly assigned to mice cages.Each treatment is tested with three replicates, i.e., in three cages often mice each. There are ten control cages each of which contains tenmice. Drugs are mixed in the diet at the dosage level indicated. Feedand water are offered ad libitum over a 12-day test period. Feed spilledis collected during the test period. At the end of the experiment thecollected feed is weighed and the mean feed consumption per cage of tenmice is determined for each treatment. The mice are weighed as a groupof ten and the weight gain is determined. The mice are sacrificed bycervical dislocation. The right uterine fat pad of each mouse isremoved. The fat pads for each cage of ten mice are weighed as a unit.

A correlation between the reduction in fat pad weights of treatedanimals and reduction in total body fat of treated animals has beenpreviously established. This relationship was established using severaltreatment groups in which the total body fat of treated animals wasdetermined and found to correlate closely with reduction in fat padweights of animals receiving the same treatment.

Results of representative experiments are presented in Table II. Thesedata indicate that compounds of the invention cause increases in growthas measured by weight gain and concomitant decreases in body fat ofexperimental animals.

                                      TABLE II                                    __________________________________________________________________________    Evaluation of test compounds for growth enhancement and reduction of fat      pad weight in mice                                                                                               Level                                                                         in diet                                                                           Gain                                                                             %     Fat pad wt                    Compound                           (ppm)                                                                             (g)                                                                              ± Control                                                                        % ± control                __________________________________________________________________________     ##STR15##                         200 100  50  25  12  6                                                            15.3 17.0 15.5 11.7 12.2 11.7                                                    +27.5 +41.7 +29.2  +2.5  +1.7                                                 +.5   -26.3 -24.5  -7.1 -19.9                                                       -12.8 -11.3                    ##STR16##                         100 13.1                                                                             +23.6 -13.5                          ##STR17##                         200 100  50  25  12  6                                                            17.3 12.9 15.5 12.1 13.5 15.1                                                    +44.3  +7.5 +29.2  +0.8 +12.5                                                 +25.8 -51.1 -36.9 -25.5 -13.2                                                       +.2  -7.0                      ##STR18##                          50 18.7                                                                             +77.4  -5.1                          ##STR19##                         200 21.4                                                                             +46.6  -7.1                          ##STR20##                         200 24.5 22.9                                                                        +67.8 +56.8                                                                          +0.6 +1.8                     ##STR21##                         200 18.4 16.9                                                                        +41.5 +30.0                                                                          +3.8 -2.4                     ##STR22##                          50 13.6                                                                              +3.8  -7.0                          ##STR23##                         200 15.0                                                                             +41.5  +4.7                          ##STR24##                         200 17.5                                                                             +65.1 -15.5                          ##STR25##                                                                     ##STR26##                                                                     ##STR27##                                                                     ##STR28##                                                                     ##STR29##                                                                    __________________________________________________________________________

I claim:
 1. A compound having the structural formula: ##STR30## whereinX is N(SO₂ R₈)₂, and R₈ is C₁ -C₄ alkyl; R₁ is hydrogen or C₁ -C₄ alkyl;R₂ is hydrogen, C₁ -C₄ alkyl, benzyl, phenethyl, α-methylphenethyl, orα,α-dimethylphenethyl; R₃ is OH; with the provisos that when R₂ isbenzyl, phenethyl, α-methylphenethyl or α,α-dimethylphenethyl, R₁ of NR₁R₂ is hydrogen; and the optically active isomers, and thepharmacologically acceptable acid addition and metal salts thereof.
 2. Acompound according to claim 1,N-{2-hydroxy-5-[1-hydroxy-2-(isopropylamino)ethyl]phenyl}dimethanesulfonamideand the optical isomers and acid addition salts thereof.
 3. A compoundaccording to claim 1,[N,[5-[2-[(α,α-dimethylphenethyl)amino]-1-hydroxyethyl]-2'-hydroxyphenethyl]dimethanesulfonamide]N-[5-[2-[(α,α-dimethylphenethyl)amino]-1-hydroxyethyl]-2-hydroxyphenyl]dimethanesulfonamideand the optical isomers and acid addition salts thereof.